Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity
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PROVIDER: PRJNA685449 | ENA |
REPOSITORIES: ENA
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Project description:Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons. Subplate neurons (SPNs), strategically positioned at the interface of cortical grey and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pan-cortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating non-cell autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate-thalamocortical axon co-fasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate-thalamocortical axon co-fasciculation and extracellular matrix assembly. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.
2021-05-06 | GSE163273 | GEO
Project description: Not available
| S-EPMC8166177 | biostudies-literature
Project description:Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
2019-11-05 | GSE126139 | GEO
Project description:Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity need to be further identified. Here, we report that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoter by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of promoter region. Our findings demonstrate the new roles of ARID1A and NSD2 in innate immunity, providing insight to the crosstalks of chromatin remodeling, histone modification and transcription factor in the epigenetic regulation of antiviral innate immunity.
2022-07-01 | GSE176452 | GEO
Project description:Although evidence indicates that the adult brain retains a considerable capacity for circuit formation, adult wiring has not been broadly considered and remains poorly understood. Here, we investigated wiring activation in adult neurons. Based on bioinformatic analyses on a previously published dataset (GSE161619), we identified the basic-helix-loop-helix (bHLH) transcription factor Ascl4 as a potential regulator of adult wiring and show that the AAV-mediated overexpression of Ascl4 can cell autonomously induce wiring in different types of hippocampal neurons of adult mice. The new axons are mainly feedforward and reconfigure synaptic weights in the hippocampal circuit. Mice with rewired circuits do not display signs of pathology and solve spatial problems equally well as controls. Our results demonstrate reprogrammed connectivity by a single transcriptional factor and provide insights into the regulation of brain connectivity in adults.
2024-05-09 | GSE246825 | GEO
Project description:The assembly of neural circuits is dependent upon precise spatiotemporal expression of cell recognition molecules1–6. Factors controlling cell-type specificity have been identified7–9, but how timing is determined remains unknown. Here we describe the induction of a cascade of transcription factors by a steroid hormone (Ecdysone) in all fly visual system neurons spanning target recognition and synaptogenesis. We demonstrate through single cell sequencing that the Ecdysone pathway regulates the expression of a common set of targets required for synaptic maturation and cell-type specific targets enriched for cell surface proteins regulating wiring specificity. Transcription factors in the cascade regulate the expression of the same wiring genes in complex ways, including activation in one cell-type and repression in another. We show that disruption of the Ecdysone-pathway generates specific defects in dendritic and axonal processes and synaptic connectivity, with the order of transcription factor expression correlating with sequential steps in wiring. We also identify shared targets of a cell-type specific transcription factor and the Ecdysone pathway which regulate specificity. We propose neurons integrate a global temporal transcriptional module with cell-type specific transcription factors to generate different cell-type specific patterns of cell recognition molecules regulating wiring.
2021-12-14 | GSE190714 | GEO
Project description:Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages
| PRJNA736309 | ENA
Project description:Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in corticohippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8 +/− mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.
2018-04-24 | GSE81103 | GEO
Project description:Chromatin remodeling and protein synthesis are tightly regulated processes that impact gene expression and cellular phenotypes. However, it is unknown if these two regulatory mechanisms are linked or exert independent effects in normal epithelial physiology and disease states. We have uncovered a new functional relationship between the chromatin remodeler ARID1A and mRNA translation elongation that is involved in maintaining cellular fitness in the context of bladder carcinogenesis. Loss of ARID1A triggers inhibition of the translation elongation factor eEF2 and ribosome accumulation, which results in a reduction in protein synthesis. In the setting of ARID1A deficiency the bladder carcinogen BBN induces DNA damage and cell death without impacting cancer initiation. As such, ARID1A is necessary for tumorigenesis. Remarkably, restoration of translation elongation through eEF2 is sufficient to initiate transformation in the context of ARID1A loss. However, dependence on ARID1A for transformation appears to be context specific, as loss of ARID1A after tumor establishment is sufficient for cancer progression.
2023-03-13 | GSE201220 | GEO
Project description:The study identifies genes that are regulated by the loss of the chromatin remodeller subunit ARID1A in colorectal cancer cell lines. This gene is frequently mutated in colorectal cancer.
2019-06-11 | E-MTAB-7791 | biostudies-arrayexpress